Middle ear pressure regulation is central to the maintenance of mucosal health and a well functioning middle ear. Regulation is achieved by the ventilatory function of the eustachian tube which, under normal conditions supplies the middle ear with a sufficient quantity of gasses to balance the net absorption by the mucosa. Disruption in this balanced supply- demand relationship causes the progressive development of middle ear underpressures, mucosal inflammation and effusion within the middle ear space. These changes, in turn cause a significant hearing loss and, if persistent may cause permanent pathologies of the middle ear ossicles, mucosa and tympanic membrane. Dysregulation can result from a decreased volume of gas exchanged with the environment during eustachian tube dilations, an increased rate of gas exchange with the mucosa and blood, or both. A knowledge of the mechanisms that control middle ear pressure regulation and of the conditions that disrupt normal functioning is fundamental to understanding the pathogenesis of otitis media with effusion and to developing rationale strategies for the prevention or treatment of that disease. The experiments included in this proposal address various aspects of middle ear pressure regulation. Specifically, they evaluate previously proposed hypotheses regarding feedback modulation of eustachian tube function, and determine the mechanism of gas exchange between middle ear, mucosa and blood under normal and disease conditions. These results will be used to refine existing models of middle ear pressure regulation; predict the behavior of middle ear pressure under a variety of conditions; develop a clinical test for the adequacy of middle ear pressure regulation, and define rational interventions for minimizing the pathological effects of dysregulation.